1. Field of the Disclosure
The disclosure relates generally to tribenzo-azacyclophanes and methods of making the same. More particularly, the disclosure is directed to tribenzo-1,4,7-triazacyclononane and related compounds, and to methods of making the same.
2. Brief Description of Related Technology
Cyclophanes are molecules having at least one aromatic group bridged by at least one hydrocarbon or substituted hydrocarbon chain. Many cyclophanes have a capacity to function as supramolecular scaffolds, and in addition, cyclophanes may recognize and bind specific molecules or ions. In host-guest chemistry, the supramolecular entity is commonly regarded as the host, and the bound ion or molecule comprises the guest. Anion-selective hosts, for example, are useful as sensors for environmentally important anion guests, such as nitrate and phosphate. In addition to their applications in analytical detection and sensing, supramolecular scaffolds are useful in fields such as materials science, catalysis, and drug delivery.
Cyclotriveratrylene (CTV) (Collet Tetrahedron 43:5725-5759 (1987)), for example, is a crown-shaped cyclophane scaffold that is readily prepared from the trimerization of veratryl alcohol in acid. CTV can bind a variety of small organic and organometallic guests within its bowl-shaped cleft, including DMSO, ethanol, chlorinated organics, xenon, lanthanides, organometallic complexes, and fullerenes such as C60 and anionic C70 dimers. CTV also has been found useful for selective anion sensing. In addition, derivatives of CTV and complexes of CTV with fullerenes are capable of forming liquid crystals.
One disadvantage of CTV is its poor water solubility. The solubility of CTV can be improved by appending polyethylene glycol substituents to CTV to form high molecular weight (>3000 to >6000 amu) derivatives. For many applications high molecular weight compounds can be unsuitable, and thus a need exists for water-soluble cyclophanes having lower molecular weights.

Several heteroatom derivatives of CTV are known. Trioxocyclononene 15 (Weiss et al. Zeitschrift fuer Naturforschung, Teil B: Anorganische Chemie, Organische Chemie, Biochemie, Biophysik, Biologie, 29:156-158 (1974), Von Deuten et al. Zeitschrift fuer Naturforschung, Teil B: Anorganische Chemie, Organische Chemie 36B:1526-1531(1981)) exhibits a crown-shaped stricture. Trithiacyclotriveratrylene 16 (Weiss et al. Zeitschrift fuer Naturforschung, Teil B: Anorganische Chemie, Organische Chemie 34B:448-450 (1979), Von Deuten et al. Crystal Structure Communications 8:569-575 (1979)) forms complexes with copper(I), rhodium(III), and platinum (II), and exists in a temperature- and solvent-dependent equilibrium of the crown and the saddle forms. The tris(dimethylsilyl) analog 17 (Sakurai et al. Chemistry Letters 595-598 (1984)) is conformationally mobile on the NMR time scale. The trimercury analog 18 (Woodard et al. Journal of Organometallic Chemistry 112:9-19 (1976)) is a planar Lewis acidic chelator that encapsulates Lewis basic halide anions. The tribenzo-1-azacyclononene derivative 19 (Zhang et al. J. Org. Chem. 70:5164-5173 (2005)) is theorized to have pharmacological activity as an anti-depressant. However, due to the presence of only a single amino group, compound 19 lacks the capability to chelate metals in the crown apex or to make carbon-capped orthoamide derivatives. Additionally, triaza[13]metacyclophane 20 (Ito et al. J. Org. Chem. 64:8236-8241 (1999)) lacks the ability to chelate metals or to make carbon-capped orthoamide derivatives due to the three-dimensional geometry enforced by meta substitution. Cyclophanes capable of chelating metals and orthoamide cyclophane derivatives are theorized to serve as new chelating ligands to modulate the properties of bound metals and advantageously bind guests with improved selectivity and/or affinity.